1. Field of the Invention
The present invention relates to a cost effective method for the manufacture of 4-amino-hydroxybutylidene-1,1-bisphosphonic acid (Formula I) and its pharmaceutically acceptable salts, particularly sodium alendronate (Formula II). This invention makes use of a cheaper raw material like pyrrolidone, eliminates the use of phosphorous acid from the phosphonating mixture, and is further characterized by its robustness, simplicity, time cycle reduction, cost effectiveness and environmental friendliness.
2. Background of the Invention
4-amino-hydroxybutylidene-1,1-bisphosphonic acid, also known as Alendronic acid (Formula I), and its sodium salt (Formula II), known as sodium alendronate, is an inhibitor of bone resorption and therefore useful for the treatment of diseases such as Paget's disease, malign hypercalcemia and osteoporosis.

The preparation of alendronic acid using phosphonation mixture such as H3PO3/PCl3, H3PO3/PCl5 and H3PO3/POCl3 are known in the literature. One such method is described in U.S. Pat. No. 4,407,761 for the preparation of alendronic acid with the above phosphonation mixtures starting from 4-aminobutyric acid (GABA); the reaction product obtained was hydrolyzed under acidic conditions to yield said product.
Another report, disclosed in U.S. Pat. No. 4,705,651, is also found to use the same starting material (GABA) and phosphonation mixture (H3PO3/PCl3) but optimizing the ratio of the GABA to H3PO3PCl3. However, the problem with the above methods is that, during reaction, local solidification of the mass occurs, which prevents mixing of the components, resulting in incomplete conversion, varying yields and therefore inconsistent outputs being observed. During hydrolysis, hot-spots were created which caused substantial risk in the operation on large scale. The reaction was also attempted in high boiling diluents such as chlorobenzene, but the yields were very poor.
Another improved version, disclosed in U.S. Pat. No. 4,922,007, describes the bisphosphonation of GABA using H3PO3/PCl3 in the presence of methane sulphonic acid to make the phoshonation reaction mass homogeneous, thus avoiding local solidification of the reaction mass. However, the hydrolysis of the reaction mass takes longer, perhaps several hours under highly acidic conditions, which became the subject of an improved process disclosed in U.S. Pat. No. 5,019,651. That patent provides an improved hydrolysis step, named as pH controlled hydrolysis, to overcome the problems in the hydrolysis step, for example, formation of a strongly acidic and highly corrosive reaction solution requiring special means, like glass lined vessels, etc., to handle it. However, the reported yield in this improvement is low, which is in the range of 50- to 63-percent based on the starting 4-aminobutyric acid (GABA).
Other reports, as disclosed in WO98/34940 and WO02/090367, disclose the use of diluents like polyethylene glycol, triglycerides of animal or plant oils, respectively, in the phosphonation reaction to solve the problems discussed above. But again, the separation of pure alendronic acid or sodium alendronate from such diluents remains difficult without having multiple purification steps.
Yet another report, U.S. Pat. No. 5,039,819, describes phosphonation of GABA comprising the steps of protecting the amino group with phthalic anhydride, activation of the acid with thionyl chloride, reacting resulting product with an alkylphosphite and finally hydrolyzing the biphosphonic ester obtained, and finally removing the protecting group (phthalimido). However, this method introduces many process steps/operations like protection, deprotection, etc., which are time consuming and generate a lot of effluent and are not desirable for industrial scale operations.
It is evident that most of the methods use similar phosphonation reactions as disclosed in U.S. Pat. No. 4,407,761, making use of phosphonation mixtures such as H3PO3/PCl3, H3PO3/PCl5 and H3PO3/POCl3 and 4-amino-butyric acid material.
An improved method was reported in Chinese Patent No. 1548442A, starting with a much cheaper starting material (compared to 4-aminobutyric acid), pyrrolidone, using 85% methane sulphonic acid and PCl3 as phosphonation reagent. This method appeared to be better, mainly on cost grounds, as the reported yields are better (81-percent). However, actual reproduction of the disclosed process resulted in varying yields and, on carefully optimized conditions, it only yielded 48-percent sodium alendronate.
Therefore, the object of the present invention is to overcome or ameliorate the problems in the prior art such as solidification, hot-spots, uncontrollable exotherms, non-homogeneous reaction conditions, incomplete reaction, etc., and to provide a high yielding and consistent process which can be scaled to industry.